RARE DISEASE
AA amyloidosis
AA amyloidosis
AA amyloidosis
Synonyms: Inflammatory amyloidosis, Reactive amyloidosis
Synonyms: Inflammatory amyloidosis, Reactive amyloidosis
Synonyms: Inflammatory amyloidosis, Reactive amyloidosis
Drug discovery
1
drug
With orphan designation
Overview
AA amyloidosis is a systemic disorder caused by chronic inflammation leading to accumulation of serum amyloid A (SAA) protein fibrils, primarily affecting the kidneys. It often complicates chronic inflammatory diseases (e.g., rheumatoid arthritis, infections, autoinflammatory syndromes), with nephrotic syndrome and renal failure as hallmark manifestations. Management focuses on controlling inflammation to reduce SAA production, using anti-cytokine therapies (e.g., IL-6 inhibitors) or immunosuppressants, aiming to halt amyloid deposition and improve outcomes [1][3][7][12].
Population
Annual incidence: 1–2 cases/million; higher in regions with endemic infections/autoimmune diseases (e.g., Middle East, Japan) [7][12].
Median age at diagnosis: 50–70 years; slight male predominance (55–60%) [7][14].
Most common triggers: Rheumatoid arthritis, familial Mediterranean fever (FMF), chronic infections (e.g., tuberculosis, osteomyelitis) [7][12].
Burden
Morbidity: >90% develop renal involvement (proteinuria, CKD); 10% present with kidney failure [7][12].
Mortality: Linked to cardiac (rare) or multiorgan failure; 5-year survival >70% with SAA control [7][19].
Risk factors: Poor prognosis with elevated SAA, hypoalbuminemia, delayed diagnosis, and infections [7][12].
Therapies
Anti-inflammatory therapy: TNF-α inhibitors, IL-1β/IL-6 blockers (e.g., tocilizumab), and immunosuppressants to suppress SAA production [3][13][18].
Targeted SAA control: Aim for SAA <10 mg/L to stabilize or reverse organ damage [7][12].
Emerging approaches: Small molecules disrupting amyloid fibrils (e.g., anti-SAA antibodies) and renal transplantation for end-stage disease [3][7].
Categories: rare cardiac diseases, rare neurological diseases, rare renal diseases, rare systemic and rheumatological diseases, rare transplant-related disorders
Research Papers
659 drug discovery papers about AA amyloidosis, with 1 first-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
659 drug discovery papers about AA amyloidosis, with 1 first-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-11 | Treatment with CFTR modulators and subsequent remission of AA amyloidosis.
Cystic fibrosis transmembrane conductance regulator (CFTR) modulators have been revolutionary for cystic fibrosis patients. Their potential influence on AA amyloidosis has not been investigated. In AA amyloidosis, patients develop amyloid deposits of serum A amyloid, in the context of a chronic inflammatory state. This case report is of a gentleman with cystic fibrosis and nephrotic range proteinuria secondary to AA amyloidosis. At 5 years following commencement of CFTR modulators, he is in sustained, complete remission with normal urine protein excretion and serum amyloid protein levels within the normal range.
2026-09-04 | AA amyloidosis in familial Mediterranean fever: a comparative study of clinical and genetic features between Algerian probands and their relatives.
AA amyloidosis is the most severe complication of familial Mediterranean fever (FMF). Why some patients develop amyloidosis while genotype-identical relatives remain unaffected is unknown. We assessed whether genetic counseling helps to identify at-risk relatives and whether inflammatory activity, rather than MEFV genotype, drives amyloidosis. We conducted a single-center comparative study (1998-2025) including 52 Algerian FMF probands with biopsy-proven AA amyloidosis and 30 first- or second-degree relatives with biallelic MEFV mutations who also had FMF but no amyloidosis. All underwent clinical, laboratory and MEFV genotyping (exons 2,3,5,10). Only individuals with two MEFV mutations (homozygous or compound heterozygous) were included. Multivariable logistic regression identified independent predictors of amyloidosis. The M694I/M694I genotype was equally frequent in both groups (71.2% vs. 66.7%, p = 0.67). In univariable analysis, it was not associated with amyloidosis (OR 1.23, 95% CI 0.48-3.16, p = 0.67). Independent drivers of amyloidosis were identified by multivariable logistic regression: attack duration > 72 h (adjusted odds ratio [aOR] 3.21, 95% CI 1.41-7.31, p = 0.006), attack interval < 3 months (aOR 4.12, 95% CI 1.77-9.58, p < 0.001), and baseline CRP > 100 mg/L (aOR 2.91, 95% CI 1.23-6.88, p = 0.014). Only 9.6% of amyloidosis patients achieved normalised CRP (< 5 mg/L) under colchicine, compared to 86.7% of relatives (p < 0.001). Strikingly, among amyloidosis patients who achieved CRP normalisation, 57.7% required 1.5 mg/day of colchicine and 7.7% required 2 mg/day, whereas 86.7% of amyloid-free relatives achieved normalisation with only 1 mg/day, highlighting the higher inflammatory burden in patients who develop amyloidosis despite carrying the same MEFV genotype. Genetic counseling allowed screening of 30 relatives without amyloidosis. Inflammation, not MEFV genotype, dictates AA amyloidosis in FMF. Genetic counseling is essential to identify at-risk relatives. Treatment should target complete CRP normalisation regardless of genotype.
2026-08-24 | Adrenal Insufficiency as the First Manifestation of AA Amyloidosis in a Patient with Familial Mediterranean Fever: A Case Report
Background: Familial Mediterranean Fever (FMF) is the most common monogenic autoinflammatory disease, and AA amyloidosis is its most severe complication. While AA amyloidosis predominantly affects the kidneys, adrenal involvement is exceptionally rare and infrequently reported. Case Presentation: A 32-year-old man on chronic hemodialysis for end-stage renal failure due to amyloid nephropathy was referred for chronic abdominal pain, hypercalcemia (> 115 mg/L), hyponatremia (130 mmol/L), and severe intradialytic hypotension. He reported that his typical FMF attacks had ceased after starting hemodialysis; however, he had recently developed new, continuous symptoms, including intense asthenia and chronic abdominal pain. Physical examination revealed progressive hyperpigmentation on sun-exposed areas. Endocrinological work-up confirmed primary adrenal insufficiency (very high ACTH with low cortisol). An abdominal CT scan showed bilateral adrenal calcifications. The patient's history included recurrent febrile episodes since childhood and a family history suggestive of FMF. AA amyloidosis was confirmed via salivary gland biopsy, and genetic testing revealed a homozygous M694I mutation in the MEFV gene. The patient was started on hydrocortisone replacement therapy. Despite initial improvement, he died one year later from complications related to advanced AA amyloidosis, including severe diarrhea and malnutrition. Conclusions: This case illustrates the rare occurrence of adrenal insufficiency due to AA amyloidosis in FMF. It highlights the need to screen for adrenal insufficiency in dialysis patients presenting with chronic abdominal pain, unexplained hypercalcemia, or intradialytic hypotension. The presence of adrenal calcifications on abdominal CT should raise suspicion for this diagnosis. Most importantly, this case underscores that FMF is prevalent in Algeria and that AA amyloidosis and its devastating complications can be prevented by early initiation of colchicine therapy in childhood. Increased awareness and early diagnosis are crucial to avert such tragic outcomes.
2026-07-03 | Amyloid exacerbates tau and alpha-synuclein pathologies, behavioral impairments, and neuroinflammation in a mixed dementia model.
Neurodegenerative diseases often involve overlapping alpha-synuclein (asyn), amyloid beta, and tau proteinopathies, yet the mechanisms, impact, and directionality of their interactions remain unclear. We induced brain-wide neuronal asyn/tau pathologies via viral expression of wild-type asyn, mutant asynE46K, mutant tauA152T, or both asynE46K/tauA152T in adult amyloidosis knock-in mice and controls, either post-plaque deposition (6 months old) or pre-plaque (3 months old). Open-field behavior was assessed baseline and 3 and 6 months post-transduction, followed by neuropathology and neuroinflammation analyses. Post-plaque induction in amyloid mice increased asyn/tau total and phosphorylated levels and exacerbated amyloid-related hyperlocomotion/anxiety. Pre-plaque induction produced robust phosphorylated pathologies irrespective of amyloid, while causing similar amyloid-dependent behavioral synergy. Tau pathology drove LGALS3+ inflammatory glial responses in white-matter fibers. Amyloid context gates vulnerability, with certain synergies manifesting across stages. White-matter gliosis is a novel mechanism of tauA152T risk. Together, our data argue for the development of stage-aware, multitarget interventions and biomarkers.
2026-07-01 | Infertility in aa renal amyloidosis secondary to familial mediterranean fever
ABSTRACT Background and Objectives: Familial Mediterranean Fever (FMF) is the most common monogenic autoinflammatory disease worldwide, affecting mainly Mediterranean populations. AA amyloidosis is its most severe complication, with renal involvement being the primary determinant of prognosis. While infertility has been historically associated with FMF, particularly before the colchicine era, the specific impact of AA amyloidosis on fertility outcomes remains poorly characterized1, 2 . This study aims to evaluate fertility in patients with FMF‑related AA amyloidosis compared to FMF patients without amyloidosis. Methods: Retrospective study of all FMF patients seen at our center over a 4‑year period (2015 to 2019). Diagnosis was established according to Livneh criteria3 . Fertility data were collected from medical records, including number of pregnancies, parity for women, and number of children for men. Patients with biopsy‑proven AA amyloidosis were compared to those without amyloidosis. Results: Eighty FMF patients were included, of whom 52 had histologically confirmed AA amyloidosis. Median age at diagnosis was 33.7 years (range 6 to 70). Median age at symptom onset was 6 years (range 4 to 45). Forty‑nine patients were homozygous or compound heterozygous for pathogenic MEFV mutations, while 31 were simple heterozygous. Median age at colchicine initiation was 38.1 years (range 28 to 70). Among men (44 patients, median age 42 years), mean number of children was 2 (range 0 to 7). Declared infertility was observed in 2 men (4.5%) within the AA amyloidosis group. Among women (36 patients, median age 37 years), mean number of pregnancies was 2.2 (range 0 to 9); 22% were under 25 years and 35% under 30 years. Infertility was diagnosed in 4 women (11.1%), all of whom had developed AA renal amyloidosis. Overall, 47 patients (58.8%) with secondary amyloidosis had children. AA amyloidosis complicating FMF significantly increased infertility risk compared to FMF patients without amyloidosis (11.5% versus 0%, p = 0.03). Conclusion: AA amyloidosis complicating FMF significantly increases infertility risk compared to FMF patients without amyloidosis. Early and sustained colchicine prescription can restore fertility rates to normal levels and prevent the development of systemic amyloidosis 4, 5 . Keywords: Familial Mediterranean fever; AA amyloidosis; infertility; colchicine; MEFV mutation; renal amyloidosis.
proteins
2026-09-25 | Renal AA amyloidosis associated with severe obesity: improvement in kidney function and proteinuria following semaglutide-associated weight loss.
AA amyloidosis is driven by persistently elevated serum amyloid A (SAA) in chronic inflammation. Severe obesity has emerged as a potential inflammatory driver of renal AA amyloidosis. We report a 47-year-old man with prior sleeve gastrectomy who developed progressive kidney dysfunction and proteinuria after substantial weight regain. At presentation, he weighed 126 kg (body mass index, 45.2 kg/m2); serum creatinine was 4.3 mg/dL (estimated glomerular filtration rate, 15 mL/min/1.73 m2) and urine albumin-to-creatinine ratio (UACR) was 3.4 g/g. Kidney biopsy confirmed AA amyloidosis, while extensive evaluation for autoimmune, infectious, hereditary, malignant, and monoclonal causes was unrevealing. SAA was 80 mg/L with persistently elevated inflammatory markers. Semaglutide was initiated as part of a weight-management strategy. Following a 47-kg weight loss, creatinine decreased to 2.34 mg/dL, estimated glomerular filtration rate increased to 32 mL/min/1.73 m2, UACR declined to 1.0 g/g, and SAA fell to <10 mg/L, with improvement in C-reactive protein, erythrocyte sedimentation rate, and HbA1c. In the absence of another identifiable cause, the parallel improvement in SAA, systemic inflammation, proteinuria, and kidney function supports severe obesity as a potential inflammatory contributor to renal AA amyloidosis, although causality cannot be inferred from a single case.
2026-09-15 | Renal Amyloidosis in Pediatric Autoinflammatory Syndromes: Subclinical Onset, Early Biomarkers, and Clues for Timely Characterization and Interventions.
Background/Objectives: Autoinflammatory syndromes are defined by episodes of recurrent fever driven by innate immune dysregulation, yet their long-term organ consequences remain largely underestimated, mostly in children. Renal AA amyloidosis represents the most perilous complication of sustained, even subclinical, inflammation, capable of progressing silently to irreversible renal failure. In pediatric cohorts, the interval between autoinflammatory disease onset and amyloidosis diagnosis spans nearly a decade, an actionable window that current surveillance frameworks have not adequately addressed. This review examines the pathophysiological continuum linking chronic cytokine overproduction to renal amyloid deposition in children with autoinflammatory syndromes, evaluates emerging subclinical biomarkers of early renal injury, identifies relevant diagnostic pitfalls, and proposes a structured renal surveillance framework for at-risk pediatric populations. Materials and Methods: This comprehensive review has been conducted analyzing studies reporting renal outcomes, biomarker data, or therapeutic interventions in pediatric patients with monogenic or polygenic autoinflammatory conditions. No date restriction was applied, with emphasis placed on publications from 2015 onward reflecting contemporary treatments and diagnostic standards. Results: An overproduction of interleukin (IL)-1β and IL-6 drives serum amyloid-A accumulation that may persist measurably during intercritical periods, preceding overt proteinuria by years in most young patients with autoinflammatory syndromes. Urinary neutrophil gelatinase-associated lipocalin (NGAL) is significantly elevated in attack-free children with familial Mediterranean fever (FMF) compared to healthy controls, representing an early and sensitive marker of tubular stress. Shear wave elastography has demonstrated measurable increases in renal tissue stiffness in pediatric FMF patients, correlating with subclinical inflammatory activity. Critically, nutcracker syndrome has emerged as the leading cause of proteinuria in colchicine-treated FMF cohorts, accounting for up to 67.5% of proteinuria cases and representing a clinically significant confounder. IL-1 inhibition with either anakinra or canakinumab has demonstrated histological regression of established amyloid deposits in different cohorts of pediatric patients, reinforcing the potential therapeutic value of earlier identification and intervention before overt irreversible glomerular damage comes out. Conclusions: Renal amyloidosis in autoinflammatory syndromes is a plausibly preventable outcome when subclinical injury is identified and treated within the pre-amyloid window in the pediatric age. Conventional reliance on 'proteinuria' as the primary surveillance threshold is potentially misleading. A biomarker-guided monitoring approach incorporating serum amyloid-A, urinary NGAL, and renal elastography might offer a clinically actionable pathway toward earlier nephrology referral and targeted IL-1 blockade, with the potential to improve renal prognosis of these children.
2026-06-23 | Structure-Guided Pegylation of IL-1RA Preserves Fold and Antagonist Function.
Rational design of PEGylated protein therapeutics requires mechanistic understanding of how coupling chemistry and PEG size jointly determine product homogeneity, receptor engagement, and structural integrity─the properties that collectively govern whether a conjugate is a viable candidate for further development. Anakinra (recombinant interleukin-1 receptor antagonist, IL-1Ra) is an approved anti-inflammatory biologic whose short systemic residence necessitates daily subcutaneous injection and is associated with steep peak-trough exposure fluctuations that, in chronic high-dose regimens, have been linked to IL-1Ra-derived systemic amyloidosis. PEGylation offers a chemically established route to increase the apparent molecular size of IL-1Ra and thereby reduce renal filtration and smooth exposure, but the structural and functional consequences of conjugation have never been characterized at residue resolution for this target─a gap that limits informed design choices between available chemistries. Here, we address this gap by establishing a head-to-head characterization framework comparing site-specific thiol-maleimide conjugation and random amino-coupling on a uniformly 15N-labeled recombinant IL-1Ra variant (M143V) that preserves all native conjugation sites and is potency-matched to Anakinra. Across a 5-20 kDa PEG ladder at a substoichiometric 0.5:1 PEG:protein feed, site-specific thiol-maleimide coupling yielded substantially higher conversion (∼81%) and a homogeneous single-species di-PEGylated (DoP 2) conjugate, whereas random amino-coupling produced heterogeneous mixtures across all PEG sizes (∼33-36% conversion, multiple degrees of polymerization). Purified single-species conjugates were benchmarked under a fixed IL-1β EC80 challenge in HEK-Blue reporter cells; all retained full maximal efficacy but exhibited chemistry- and size-dependent right-shifts in IC50, indicating steric modulation of receptor engagement rather than loss of function. To directly establish whether PEG attachment perturbs structural integrity, 2D 1H-15N HSQC NMR on the 15N-labeled thiol-PEG10 conjugate demonstrated a preserved global fold with localized chemical-shift perturbations near cysteine-proximal surface regions, confirming site-selective modification and intact binding scaffold. Together, these data establish the conjugation quality, antagonist activity, and structural integrity of the lead conjugate as the prerequisite characterization foundation for its further development and provide a transferable analytical framework for the rational design of PEGylated cytokine therapeutics.
2026-06-12 | Prolonged Infections and Inflammatory Diseases in Common Variable Immune Deficiency as a Cause of AA Amyloidosis.
Background/Objectives: AA amyloidosis is a serious complication of chronic inflammation, which may arise in the setting of inborn errors of immunity (IEIs) due to recurrent or persistent infections. Common variable immunodeficiency (CVID) is the most frequent symptomatic IEI in adults, yet its association with secondary AA amyloidosis remains rarely reported. Case presentation: We describe a 37-year-old male with a history of recurrent pneumonia, chronic sinusitis, and osteomyelitis with sepsis since childhood. At age 33, he developed bilateral pneumonia after COVID-19, followed by repeated lower respiratory tract infections. At age 36, nephrotic syndrome (proteinuria 10.69 g/day, hypoalbuminemia) led to kidney and gastric mucosa biopsies, which confirmed AA amyloidosis. Immunological workup revealed panhypogammaglobulinemia (IgG 0.1 g/L, IgA 0.01 g/L, IgM 0.28 g/L), markedly reduced switched memory B cells, and an inverted CD4+/CD8+ ratio. Chest CT showed bronchiectasis, bronchiolitis, and mediastinal lymphadenopathy. Whole-exome sequencing excluded known monogenic IEIs, autoinflammatory, or hereditary amyloidosis genes; a heterozygous likely pathogenic variant in ODAD2 (associated with primary ciliary dyskinesia) was considered incidental. A diagnosis of CVID with secondary AA amyloidosis was established. Conclusions: This case illustrates that CVID may remain undiagnosed for decades and present with secondary AA amyloidosis as the first major complication. In any patient with nephrotic syndrome and a history of recurrent or unusual infections, an IEI should be actively excluded. Early recognition of CVID and appropriate immunoglobulin replacement therapy can prevent infectious exacerbations and potentially halt amyloid progression.
2026-05-25 | Proline-rich, polybasic peptides are a structurally distinct class of amyloid-reactive peptides.
Systemic amyloidosis is a chronic, devastating illness caused by the build-up of misfolded proteins, leading to abdominothoracic organ dysfunction. Currently approved treatment options focus on preventing further amyloid accumulation. As such, there is a clinically unmet need for therapeutics that can opsonize tissue-deposited amyloid for clearance by phagocytic cells. We have developed a class of polybasic peptides that bind conserved properties of amyloid and amyloid-associated hypersulfated heparan sulfate, with high specificity. We have generated a novel structural class of polybasic peptides (termed PxR peptides) based on a proline-rich repeat strategy that demonstrates potency against amyloid. Amyloid-reactivity and specificity were probed using amyloid-laden and control tissue sections from mice and humans. Amyloid binding to synthetic fibrils and human patient-derived amyloid extracts was quantified using immunosorbent assays. PxR peptide stability in mouse and human serum was quantified using a bioactivity assay. PxR peptides were predicted to form a linear face of positive charges, which can bind with high specificity and potency to synthetic fibrils and amyloid extracts, and are resistant to serum proteases. Polybasic PxR peptides offer additional resources as pan-amyloid binding peptides for effective delivery of bioactive and amyloid-clearing therapeutics to amyloid.
antibodies
2026-08-29 | AA Amyloidosis Revealing HHV-8-Associated Multicentric Castleman Disease: A Case Report and Literature Review
Background/Objectives: Multicentric Castleman disease (MCD) is a rare systemic lymphoproliferative disorder driven by interleukin-6 (IL-6) dysregulation and frequently associated with human herpesvirus 8 (HHV-8) infection. AA amyloidosis is a severe complication of chronic inflammatory states, resulting from extracellular deposition of serum amyloid A (SAA) protein. We report a case of HHV-8-associated MCD revealed by AA amyloidosis with hepatic and salivary gland involvement. Methods: A 40-year-old Algerian woman with a six-year history of progressive gastrointestinal symptoms and chronic inflammation was evaluated for biopsy-proven AA amyloidosis involving the liver and minor salivary glands. Diagnostic workup included HHV-8 PCR, autoantibody screening, MEFV gene mutation analysis, bone marrow examination, and CT imaging. Results: HHV-8 viremia was positive (25,000 copies/mL), while autoimmune and genetic testing, including MEFV mutation screening, were negative. Clinical findings included chronic hypotension, normocytic anemia with hemolytic features, and subcentimeter lymphadenopathy on CT. A diagnosis of HHV-8-associated MCD with secondary AA amyloidosis was established. The patient was treated with rituximab (375 mg/m² weekly for four weeks) combined with valganciclovir, resulting in viral clearance, normalization of inflammatory markers, and improvement in hemoglobin. Conclusions: MCD should be considered in patients with unexplained chronic inflammation and AA amyloidosis. Early recognition and targeted therapy with rituximab are essential to prevent irreversible organ damage. Excisional lymph node biopsy with HHV-8 immunostaining is critical for definitive diagnosis.
2026-08-01 | Idiopathic AA Renal Amyloidosis Treated with Tocilizumab — A Case Report
Background Amyloidosis represents a heterogeneous group of disorders characterized by the deposition of misfolded protein. Among its subtypes, serum amyloid A (AA) amyloidosis arises when persistent systemic inflammation drives hepatic production of SAA. Excess SAA misfolds into insoluble fibrils that deposit in organs such as the kidneys, causing progressive proteinuria, loss of renal function and eventual renal failure. Standard management aims to control the underlying inflammation to reduce SAA production and halt further amyloid deposition. For example, interleukin-6 blockade with tocilizumab, which suppresses SAA production, has shown encouraging results in small series of patients with secondary amyloidosis. [1,2] In rare cases without an identifiable source of inflammation, however, no targeted therapies have been shown to be effective. Case Report We report a 48-year-old female first found incidentally at the age of 37 to have renal impairment. Over the past decade, her eGFR had declined to 12mL/min/1.73m 2 , with 3g/L of proteinuria. Renal biopsy in 2020 confirmed widespread AA amyloid deposits with severe interstitial fibrosis and 11/16 glomeruli globally sclerosed, with SAA concentrations exceeding 16,000ng/mL. Throughout her entire course, she had no infectious, rheumatologic or constitutional symptoms. Other than a RF titer of 30 IUx103/L, extensive investigations were negative, including bone marrow biopsy, rheumatologic markers (CCP, ANA, dsDNA, C3/C4, ANCA, ESR, CRP) and infectious serologies (hepatitis, syphilis, schistosoma, strongyloides, whipples, tuberculosis, HIV, HTLV, filariasis). A thorough genetic investigation was also negative including sequencing for the SAA1 gene, panels containing genes associated with hereditary amyloidosis and autoinflammatory diseases, as well as a research exome. A brief trial of colchicine was initially trialed but stopped due to worsening kidney function. Tocilizumab 160mg SC every 2 weeks was initiated in December 2024 in an attempt to suppress hepatic SAA production. A year after, SAA levels fell from >16,000 to 5,427ng/mL. Her GFR stabilized at 13 mL/min/1.73m 2 , and dialysis has not yet been required at the time of writing. Conclusion Idiopathic AA amyloidosis is a therapeutic challenge due to the condition’s rarity and lack of standard therapies. While there are numerous publications demonstrating the efficacy of tocilizumab in secondary AA amyloidosis,[1-3] our case is the first we are aware of, describing this therapeutic effect in idiopathic AA amyloidosis. This case underscores the central role of interleukin-6 in SAA production and may form the foundation for future studies with more patients over a longer duration to further explore the disease-modifying benefits of tocilizumab in idiopathic AA amyloidosis. References [1.] Okuda Y. Mod Rheumatol 2019;29:268-74. [2.] Courties A. Amyloid 2015;22:84-92. [3.] Yamagata A. BMC Nephrol 2017;18:377.
2026-07-01 | AA Amyloidosis in Africa: Epidemiology, Etiologies, Diagnostic Gaps, and Therapeutic Perspectives
ABSTRACT This review synthesizes epidemiological data from Algeria (378 cases), Tunisia (310 cases), Morocco (30 cases), Egypt (40 cases) and sub‑Saharan Africa (autopsy incidence 0.28‑0.57%). Tuberculosis remains the leading cause in all Maghreb countries, while Algeria shows a documented increase in autoinflammatory diseases; familial Mediterranean fever (FMF) predominates as the leading cause in Egypt. Diagnostic gaps include the absence of mass spectrometry in all African countries, limited anti‑AA immunohistochemistry in sub‑Saharan Africa, and no routine SAP scintigraphy. Therapeutic access is highly contrasted: adalimumab is available in several Maghreb countries, anakinra in Algeria (TRAPS approval 2025), and canakinumab is virtually absent. We propose national registries (based on the Egyptian FMF registry and the Armenian NAREG model), South‑North telepathology, and expanded access to biotherapies through biosimilars. Keywords: AA amyloidosis, Africa, diagnosis, SAP scintigraphy, Congo red, tuberculosis, FMF, autoinflammatory diseases, biotherapies.
2026-07-01 | The antibody-peptide fusion protein, AT-02, is an effective opsonin with pan-amyloid reactivity.
In systemic amyloidosis, the progressive accumulation of amyloid fibrils along with extracellular matrix components causes organ dysfunction, reduced quality of life, and is often fatal. Currently, twenty different proteins have been identified in systemic amyloid fibrils. Therapeutic elimination of tissue amyloid may improve organ function and patient outcomes. Amyloid-reactive immunoglobulins capable of stimulating cell-mediated clearance of amyloid deposits represent promising therapeutic strategies. AT-02 (zamubafusp alfa) is an immunoglobulin-peptide fusion protein comprising a humanized IgG1 and a pan-amyloid reactive peptide, p5R. AT-02 binds two ubiquitous components of all amyloids, namely amyloid fibrils and highly sulfated heparan sulfate glycans. This fusion protein exhibits specific reactivity with many amyloid types, obviating the need for individualized immunoglobulins for therapy. We demonstrate that AT-02 is an effective opsonin for amyloid by enhancing phagocytosis of amyloid extracts and inducing complement fixation. These data suggest that pan-amyloid binding reagents may provide novel treatment options for amyloid removal.
2026-06-25 | Inflammation in Cardiomyopathies: Cellular Mechanisms Across Cardiac Phenotype.
Cardiomyopathies are traditionally classified by structural and genetic phenotypes, but emerging evidence highlights chronic myocardial inflammation as a pivotal driver of disease progression across different etiologies. This review synthesizes the current literature on the cellular and molecular inflammatory mechanisms underlying hypertrophic cardiomyopathy, Anderson-Fabry disease, cardiac amyloidosis, arrhythmogenic cardiomyopathy, and dilated cardiomyopathy. Across these distinct conditions, endogenous triggers such as metabolic substrates, misfolded amyloid fibrils, mechanical stress, or viral genomes act as damage-associated molecular patterns. These stimuli activate innate and adaptive immune cascades, notably the Toll-like receptors, the NF-κB pathway, and the NLRP3 inflammasome. This immune activation establishes a pro-inflammatory microenvironment that promotes fibroblast reprogramming, myocardial edema, and progressive fibrotic or fibro-fatty remodeling. Inflammation is an active, core pathophysiological mechanism rather than a passive secondary bystander in cardiomyopathies. Recognizing these shared immune pathways provides a framework for improved risk stratification and highlights the potential for targeted immunomodulatory therapies to alter disease trajectories.
cell therapies
2026-03-23 | Development and characterization of chimeric antigen receptor macrophages for amyloid clearance.
Systemic amyloidosis is a protein folding disorder characterized by the extracellular deposition of protein fibrils in tissues and vital organs, leading to dysfunction and mortality. While there are monoclonal antibody-based therapies that promote cell-mediated amyloid clearance in various stages of clinical development, there are currently no treatment options which focus on reducing the tissue amyloid burden. Therefore, the urgent need for a transformative approach to facilitate amyloid clearance and restore organ function remains paramount. We demonstrate that a short, polybasic peptide (p5) can serve as a versatile recognition motif for chimeric antigen receptors in macrophages, enabling pan-amyloid binding and uptake. By comparing CH2- and CH3-spacer designs, quantifying glycan interactions, and establishing opsonization- and complement-dependent enhancement, we provide a blueprint for peptide-targeted CAR-M engineering beyond conventional scFv recognition. These findings broaden the repertoire of CAR targeting strategies and motivate translational studies of CAR-M for systemic amyloidosis, where established fibrils persist despite precursor-lowering therapies.
2024-02-26 | Kidney Transplantation in Patients With AA Amyloidosis: Outcomes in a French Multicenter Cohort.
Outcomes of kidney transplantation for patients with renal AA amyloidosis are uncertain, with reports of poor survival and high rates of disease recurrence. However, the data are inconclusive and mostly based on studies from the early 2000s and earlier. Retrospective multicenter cohort study. We searched the French national transplant database to identify all patients with renal AA amyloidosis who underwent kidney transplantation between 2008 and 2018. Age, cause of amyloidosis, use of biotherapies, and C-reactive protein levels. Outcomes were all-cause mortality and allograft loss. We also reported amyloidosis allograft recurrence, occurrence of acute rejection episodes, as well as infectious, cardiovascular, and neoplastic disease events. Kaplan-Meier estimator for mortality and cumulative incidence function method for allograft loss. Factors associated with patient and allograft survival were investigated using a Cox proportional hazards model and a cause-specific hazards model, respectively. 86 patients who received kidney transplants for AA amyloidosis at 26 French centers were included. The median age was 49.4 years (IQR, 39.7-61.1). The main cause of amyloidosis was familial Mediterranean fever (37 cases; 43%). 16 (18.6%) patients received biotherapy after transplantation. Patient survival rates were 94.0% (95% CI, 89.1-99.2) at 1 year and 85.5% (77.8-94.0) at 5 years after transplantation. Cumulative incidences of allograft loss were 10.5% (4.0-17.0) at 1 year and 13.0% (5.8-20.1) at 5 years after transplantation. Histologically proven AA amyloidosis recurrence occurred in 5 transplants (5.8%). An infection requiring hospitalization developed in 55.8% of cases, and there was a 27.9% incidence of acute allograft rejection. Multivariable analysis showed that C-reactive protein concentration at the time of transplantation was associated with patient survival (HR, 1.01; 95% CI, 1.00-1.02; P=0.01) and allograft survival (HR, 1.68; 95% CI, 1.10-2.57; P=0.02). The study lacked a control group, and the effect of biotherapies on transplantation outcomes could not be explored. This relatively contemporary cohort of patients who received a kidney transplant for AA amyloidosis experienced favorable rates of survival and lower recurrence rates than previously reported. These data support the practice of treating these patients with kidney transplantation for end-stage kidney disease. AA amyloidosis is a severe and rare disease. Kidney involvement is frequent and leads to end-stage kidney disease. Because of the involvement of other organs, these patients are often frail, which has raised concerns about their suitability for kidney transplantation. We reviewed all patients with AA amyloidosis nephropathy who underwent kidney transplantation in France in the recent era (2008-2018) and found that the outcomes after kidney transplantation were favorable, with 85.5% of patients still alive 5 years after transplantation, a survival rate that is comparable to the outcomes of patients receiving a transplant for other forms of kidney diseases. Recurrence of amyloidosis in the transplanted kidney was infrequent (5.8%). These data support the practice of kidney transplantation for patients with AA amyloidosis who experience kidney failure.
2024-01-12 | Extracellular vesicles as next-generation therapeutics and biomarkers in amyloidosis: a new frontier
Nanoparticles hold a great potential for therapeutic targeting due to their ability to improve the stability of encapsulated cargo and promote the transport of cargo across membranes to reach to the target site. Most commercially available nanomedicines are simple synthetic liposomes, however, there are numerous side effects due to their off-target delivery and rapid clearance from the bloodstream. Recently, attention has moved toward extracellular vesicles (EVs)–lipid bilayer enclosed particles released by cells (size ranging from 30 to 10,000 nm in diameter). EVs carry and transport lipids, proteins, and nucleic acids from their parental cells to recipient cells, hence they play a key role in intercellular communication. The ability of EVs to cross biological barriers including the blood brain barrier has generated significant attention to explore them as potential biomarkers and natural drug delivery vehicles for various therapeutics and small molecules. EVs have also been implicated in disease pathogenesis by transmitting pathogenic proteins between cells, making them promising biomarkers for disease diagnosis and monitoring. In this review, we will focus on the potential and challenges of EVs as biomarkers, drug delivery vehicles and next-generation therapeutics. Finally, we will explore misfolded protein disorders, amyloidosis, as a case study for how EVs may contribute to disease pathology and how EVs could be applied in the clinic as diagnostic and prognostic biomarkers of amyloid diseases.
2021-06-30 | Serum Amyloid A1 Induces Classically Activated Macrophages: A Role for Enhanced Fibril Formation
AA amyloidosis belongs to the group of amyloid diseases which can follow chronic inflammatory conditions of various origin. The disease is characterized by the deposition of insoluble amyloid fibrils formed by serum amyloid A1 (SAA1) leading eventually to organ failure. Macrophages are intimately involved in the fibrillogenesis as well as in the clearance of amyloid fibrils. In vivo, macrophages may occur as classically (M1) or alternatively activated (M2) macrophages. We investigate here how SAA1 might affect the macrophage phenotype and function. Gene microarray analysis revealed upregulation of 64 M1-associated genes by SAA1. M1-like polarization was further confirmed by the expression of the M1-marker MARCO, activation of the NF-κB transcription factor, and secretion of the M1-cytokines TNF-α, IL-6, and MCP-1. Additionally, we demonstrate here that M1-polarized macrophages exhibit enhanced fibrillogenic activity towards SAA1. Based on our data, we propose reconsideration of the currently used cellular amyloidosis models towards an in vitro model employing M1-polarized macrophages. Furthermore, the data suggest macrophage repolarization as potential intervention strategy in AA amyloidosis.
2021-05-14 | Kidney transplantation as a treatment of choice for AA amyloidosis due to periodic fever syndrome.
Renal AA amyloidosis is the most serious complication of periodic fever syndrome, which, inadequate suppression, due to persistent inflammation, leads to nephrotic syndrome and renal failure over several years. In most cases, periodic fever syndromes begin to manifest clinically in early childhood. Occurrence in adulthood is considered rare and is associated with a poorer clinical course. Kidney transplantation (KT) is an effective and safe treatment for end-stage chronic kidney disease (CKD) based on AA amyloidosis. In this paper, we present cases of two patients after deceased donor KT, who have been diagnosed with adult periodic fever syndrome. In the first one, diagnosis and treatment began in advanced stage of CKD and therefore underwent KT with compensated disease, while in the second patient, the disease manifested and diagnosed in the post-KT period. Timely initiation of treatment ensured protection of the graft from amyloid deposition.
other
2025-12-01 | Gene immunotherapy regulated by astrocytic reactivity in a mouse model of amyloidosis
These results suggest that the GFAP promoter could control the production of therapeutics, such as rSol, in response to amyloid-induced astrocytic reactivity. Long-term studies will assess whether rSol prevents Aβ pathology progression in Tg-Aβ mice.
2005-04-20 | In vivo fragmentation of heparan sulfate by heparanase overexpression renders mice resistant to amyloid protein A amyloidosis.
Amyloid diseases encompass >20 medical disorders that include amyloid protein A (AA) amyloidosis, Alzheimer's disease, and type 2 diabetes. A common feature of these conditions is the selective organ deposition of disease-specific fibrillar proteins, along with the sulfated glycosaminoglycan, heparan sulfate. We have generated transgenic mice that overexpress human heparanase and have tested their susceptibility to amyloid induction. Drastic shortening of heparan sulfate chains was observed in heparanase-overproducing organs, such as liver and kidney. These sites selectively escaped amyloid deposition on experimental induction of inflammation-associated AA amyloidosis, as verified by lack of material staining with Congo Red, as well as lack of associated polysaccharide, whereas the same tissues from control animals were heavily infiltrated with amyloid. By contrast, the spleens of transgenic mice that failed to significantly overexpress heparanase contained heparan sulfate chains similar in size to those of control spleen and remained susceptible to amyloid deposition. Our findings provide direct in vivo evidence that heparan sulfate is essential for the development of amyloid disease.
1995-06-01 | Linkage of protection against amyloid fibril formation in the mouse to a single, autosomal dominant gene.
Inbred strains of mice provide a model for studies of the pathogenesis of amyloid A (AA) amyloidosis. All susceptible strains of mice described to date codominantly express two serum amyloid A (apoSAA) isoforms, apoSAA1 and apoSAA2, of which only apoSAA2 serves as a precursor for amyloid fibrils. In previous studies, we have shown that the CE/J strain, which produces a single, novel apoSAA isoform, apoSAACE/J, is amyloid resistant. In the present study amyloid-resistant CE/J females were mated with amyloid-susceptible CBA/J males to produce F1 hybrid offspring which were then backcrossed to the parental CBA/J mouse strain. Amyloid susceptibility was determined in 30 backcrossed mice 72 h after injection of murine amyloid enhancing factor and silver nitrate. ApoSAA isoforms in plasma were separated by isoelectric focusing gel electrophoresis and visualized after immunoblotting with anti-AA antiserum. Amyloid A fibrils in spleen homogenates were denatured by formic acid and AA protein was quantified by ELISA using anti-mouse apoSAA antibodies. Values < 5 apoSAA equivalent units were considered negative. 13 mice expressed an apoSAA1 and apoSAA2 doublet characteristic of CBA/J mice, whereas 17 mice, expressed the apoSAACE/J isoform codominantly with apoSAA1 and apoSAA2. The correlation of amyloid resistance to expression of the apoSAACE/J isoform was absolute (17/17 were negative; mean score 2.6 +/- 0.17 [standard error of the mean] apoSAA equivalent units) and the correlation between amyloid susceptibility and the expression of apoSAA2/apoSAA1 was also striking (12/13 were amyloid positive; mean score 47.9 +/- 9.0 [standard error of the mean] apoSAA equivalent units (P < 0.001). This is not significantly different from the 50% segregation of apoSAA phenotypes expected for linkage to a single gene. These results indicate that a single gene governs apoSAACE/J expression and thus confers protection against amyloid deposition even in the presence of apoSAA1 and apoSAA2 isoforms and show for the first time that resistance to AA amyloidosis is a dominant trait governed by a single gene.
small molecules
2026-09-11 | Treatment with CFTR modulators and subsequent remission of AA amyloidosis.
Cystic fibrosis transmembrane conductance regulator (CFTR) modulators have been revolutionary for cystic fibrosis patients. Their potential influence on AA amyloidosis has not been investigated. In AA amyloidosis, patients develop amyloid deposits of serum A amyloid, in the context of a chronic inflammatory state. This case report is of a gentleman with cystic fibrosis and nephrotic range proteinuria secondary to AA amyloidosis. At 5 years following commencement of CFTR modulators, he is in sustained, complete remission with normal urine protein excretion and serum amyloid protein levels within the normal range.
2026-09-04 | AA amyloidosis in familial Mediterranean fever: a comparative study of clinical and genetic features between Algerian probands and their relatives.
AA amyloidosis is the most severe complication of familial Mediterranean fever (FMF). Why some patients develop amyloidosis while genotype-identical relatives remain unaffected is unknown. We assessed whether genetic counseling helps to identify at-risk relatives and whether inflammatory activity, rather than MEFV genotype, drives amyloidosis. We conducted a single-center comparative study (1998-2025) including 52 Algerian FMF probands with biopsy-proven AA amyloidosis and 30 first- or second-degree relatives with biallelic MEFV mutations who also had FMF but no amyloidosis. All underwent clinical, laboratory and MEFV genotyping (exons 2,3,5,10). Only individuals with two MEFV mutations (homozygous or compound heterozygous) were included. Multivariable logistic regression identified independent predictors of amyloidosis. The M694I/M694I genotype was equally frequent in both groups (71.2% vs. 66.7%, p = 0.67). In univariable analysis, it was not associated with amyloidosis (OR 1.23, 95% CI 0.48-3.16, p = 0.67). Independent drivers of amyloidosis were identified by multivariable logistic regression: attack duration > 72 h (adjusted odds ratio [aOR] 3.21, 95% CI 1.41-7.31, p = 0.006), attack interval < 3 months (aOR 4.12, 95% CI 1.77-9.58, p < 0.001), and baseline CRP > 100 mg/L (aOR 2.91, 95% CI 1.23-6.88, p = 0.014). Only 9.6% of amyloidosis patients achieved normalised CRP (< 5 mg/L) under colchicine, compared to 86.7% of relatives (p < 0.001). Strikingly, among amyloidosis patients who achieved CRP normalisation, 57.7% required 1.5 mg/day of colchicine and 7.7% required 2 mg/day, whereas 86.7% of amyloid-free relatives achieved normalisation with only 1 mg/day, highlighting the higher inflammatory burden in patients who develop amyloidosis despite carrying the same MEFV genotype. Genetic counseling allowed screening of 30 relatives without amyloidosis. Inflammation, not MEFV genotype, dictates AA amyloidosis in FMF. Genetic counseling is essential to identify at-risk relatives. Treatment should target complete CRP normalisation regardless of genotype.
2026-08-24 | Adrenal Insufficiency as the First Manifestation of AA Amyloidosis in a Patient with Familial Mediterranean Fever: A Case Report
Background: Familial Mediterranean Fever (FMF) is the most common monogenic autoinflammatory disease, and AA amyloidosis is its most severe complication. While AA amyloidosis predominantly affects the kidneys, adrenal involvement is exceptionally rare and infrequently reported. Case Presentation: A 32-year-old man on chronic hemodialysis for end-stage renal failure due to amyloid nephropathy was referred for chronic abdominal pain, hypercalcemia (> 115 mg/L), hyponatremia (130 mmol/L), and severe intradialytic hypotension. He reported that his typical FMF attacks had ceased after starting hemodialysis; however, he had recently developed new, continuous symptoms, including intense asthenia and chronic abdominal pain. Physical examination revealed progressive hyperpigmentation on sun-exposed areas. Endocrinological work-up confirmed primary adrenal insufficiency (very high ACTH with low cortisol). An abdominal CT scan showed bilateral adrenal calcifications. The patient's history included recurrent febrile episodes since childhood and a family history suggestive of FMF. AA amyloidosis was confirmed via salivary gland biopsy, and genetic testing revealed a homozygous M694I mutation in the MEFV gene. The patient was started on hydrocortisone replacement therapy. Despite initial improvement, he died one year later from complications related to advanced AA amyloidosis, including severe diarrhea and malnutrition. Conclusions: This case illustrates the rare occurrence of adrenal insufficiency due to AA amyloidosis in FMF. It highlights the need to screen for adrenal insufficiency in dialysis patients presenting with chronic abdominal pain, unexplained hypercalcemia, or intradialytic hypotension. The presence of adrenal calcifications on abdominal CT should raise suspicion for this diagnosis. Most importantly, this case underscores that FMF is prevalent in Algeria and that AA amyloidosis and its devastating complications can be prevented by early initiation of colchicine therapy in childhood. Increased awareness and early diagnosis are crucial to avert such tragic outcomes.
2026-07-03 | Amyloid exacerbates tau and alpha-synuclein pathologies, behavioral impairments, and neuroinflammation in a mixed dementia model.
Neurodegenerative diseases often involve overlapping alpha-synuclein (asyn), amyloid beta, and tau proteinopathies, yet the mechanisms, impact, and directionality of their interactions remain unclear. We induced brain-wide neuronal asyn/tau pathologies via viral expression of wild-type asyn, mutant asynE46K, mutant tauA152T, or both asynE46K/tauA152T in adult amyloidosis knock-in mice and controls, either post-plaque deposition (6 months old) or pre-plaque (3 months old). Open-field behavior was assessed baseline and 3 and 6 months post-transduction, followed by neuropathology and neuroinflammation analyses. Post-plaque induction in amyloid mice increased asyn/tau total and phosphorylated levels and exacerbated amyloid-related hyperlocomotion/anxiety. Pre-plaque induction produced robust phosphorylated pathologies irrespective of amyloid, while causing similar amyloid-dependent behavioral synergy. Tau pathology drove LGALS3+ inflammatory glial responses in white-matter fibers. Amyloid context gates vulnerability, with certain synergies manifesting across stages. White-matter gliosis is a novel mechanism of tauA152T risk. Together, our data argue for the development of stage-aware, multitarget interventions and biomarkers.
2026-07-01 | Infertility in aa renal amyloidosis secondary to familial mediterranean fever
ABSTRACT Background and Objectives: Familial Mediterranean Fever (FMF) is the most common monogenic autoinflammatory disease worldwide, affecting mainly Mediterranean populations. AA amyloidosis is its most severe complication, with renal involvement being the primary determinant of prognosis. While infertility has been historically associated with FMF, particularly before the colchicine era, the specific impact of AA amyloidosis on fertility outcomes remains poorly characterized1, 2 . This study aims to evaluate fertility in patients with FMF‑related AA amyloidosis compared to FMF patients without amyloidosis. Methods: Retrospective study of all FMF patients seen at our center over a 4‑year period (2015 to 2019). Diagnosis was established according to Livneh criteria3 . Fertility data were collected from medical records, including number of pregnancies, parity for women, and number of children for men. Patients with biopsy‑proven AA amyloidosis were compared to those without amyloidosis. Results: Eighty FMF patients were included, of whom 52 had histologically confirmed AA amyloidosis. Median age at diagnosis was 33.7 years (range 6 to 70). Median age at symptom onset was 6 years (range 4 to 45). Forty‑nine patients were homozygous or compound heterozygous for pathogenic MEFV mutations, while 31 were simple heterozygous. Median age at colchicine initiation was 38.1 years (range 28 to 70). Among men (44 patients, median age 42 years), mean number of children was 2 (range 0 to 7). Declared infertility was observed in 2 men (4.5%) within the AA amyloidosis group. Among women (36 patients, median age 37 years), mean number of pregnancies was 2.2 (range 0 to 9); 22% were under 25 years and 35% under 30 years. Infertility was diagnosed in 4 women (11.1%), all of whom had developed AA renal amyloidosis. Overall, 47 patients (58.8%) with secondary amyloidosis had children. AA amyloidosis complicating FMF significantly increased infertility risk compared to FMF patients without amyloidosis (11.5% versus 0%, p = 0.03). Conclusion: AA amyloidosis complicating FMF significantly increases infertility risk compared to FMF patients without amyloidosis. Early and sustained colchicine prescription can restore fertility rates to normal levels and prevent the development of systemic amyloidosis 4, 5 . Keywords: Familial Mediterranean fever; AA amyloidosis; infertility; colchicine; MEFV mutation; renal amyloidosis.
proteins
2026-09-25 | Renal AA amyloidosis associated with severe obesity: improvement in kidney function and proteinuria following semaglutide-associated weight loss.
AA amyloidosis is driven by persistently elevated serum amyloid A (SAA) in chronic inflammation. Severe obesity has emerged as a potential inflammatory driver of renal AA amyloidosis. We report a 47-year-old man with prior sleeve gastrectomy who developed progressive kidney dysfunction and proteinuria after substantial weight regain. At presentation, he weighed 126 kg (body mass index, 45.2 kg/m2); serum creatinine was 4.3 mg/dL (estimated glomerular filtration rate, 15 mL/min/1.73 m2) and urine albumin-to-creatinine ratio (UACR) was 3.4 g/g. Kidney biopsy confirmed AA amyloidosis, while extensive evaluation for autoimmune, infectious, hereditary, malignant, and monoclonal causes was unrevealing. SAA was 80 mg/L with persistently elevated inflammatory markers. Semaglutide was initiated as part of a weight-management strategy. Following a 47-kg weight loss, creatinine decreased to 2.34 mg/dL, estimated glomerular filtration rate increased to 32 mL/min/1.73 m2, UACR declined to 1.0 g/g, and SAA fell to <10 mg/L, with improvement in C-reactive protein, erythrocyte sedimentation rate, and HbA1c. In the absence of another identifiable cause, the parallel improvement in SAA, systemic inflammation, proteinuria, and kidney function supports severe obesity as a potential inflammatory contributor to renal AA amyloidosis, although causality cannot be inferred from a single case.
2026-09-15 | Renal Amyloidosis in Pediatric Autoinflammatory Syndromes: Subclinical Onset, Early Biomarkers, and Clues for Timely Characterization and Interventions.
Background/Objectives: Autoinflammatory syndromes are defined by episodes of recurrent fever driven by innate immune dysregulation, yet their long-term organ consequences remain largely underestimated, mostly in children. Renal AA amyloidosis represents the most perilous complication of sustained, even subclinical, inflammation, capable of progressing silently to irreversible renal failure. In pediatric cohorts, the interval between autoinflammatory disease onset and amyloidosis diagnosis spans nearly a decade, an actionable window that current surveillance frameworks have not adequately addressed. This review examines the pathophysiological continuum linking chronic cytokine overproduction to renal amyloid deposition in children with autoinflammatory syndromes, evaluates emerging subclinical biomarkers of early renal injury, identifies relevant diagnostic pitfalls, and proposes a structured renal surveillance framework for at-risk pediatric populations. Materials and Methods: This comprehensive review has been conducted analyzing studies reporting renal outcomes, biomarker data, or therapeutic interventions in pediatric patients with monogenic or polygenic autoinflammatory conditions. No date restriction was applied, with emphasis placed on publications from 2015 onward reflecting contemporary treatments and diagnostic standards. Results: An overproduction of interleukin (IL)-1β and IL-6 drives serum amyloid-A accumulation that may persist measurably during intercritical periods, preceding overt proteinuria by years in most young patients with autoinflammatory syndromes. Urinary neutrophil gelatinase-associated lipocalin (NGAL) is significantly elevated in attack-free children with familial Mediterranean fever (FMF) compared to healthy controls, representing an early and sensitive marker of tubular stress. Shear wave elastography has demonstrated measurable increases in renal tissue stiffness in pediatric FMF patients, correlating with subclinical inflammatory activity. Critically, nutcracker syndrome has emerged as the leading cause of proteinuria in colchicine-treated FMF cohorts, accounting for up to 67.5% of proteinuria cases and representing a clinically significant confounder. IL-1 inhibition with either anakinra or canakinumab has demonstrated histological regression of established amyloid deposits in different cohorts of pediatric patients, reinforcing the potential therapeutic value of earlier identification and intervention before overt irreversible glomerular damage comes out. Conclusions: Renal amyloidosis in autoinflammatory syndromes is a plausibly preventable outcome when subclinical injury is identified and treated within the pre-amyloid window in the pediatric age. Conventional reliance on 'proteinuria' as the primary surveillance threshold is potentially misleading. A biomarker-guided monitoring approach incorporating serum amyloid-A, urinary NGAL, and renal elastography might offer a clinically actionable pathway toward earlier nephrology referral and targeted IL-1 blockade, with the potential to improve renal prognosis of these children.
2026-06-23 | Structure-Guided Pegylation of IL-1RA Preserves Fold and Antagonist Function.
Rational design of PEGylated protein therapeutics requires mechanistic understanding of how coupling chemistry and PEG size jointly determine product homogeneity, receptor engagement, and structural integrity─the properties that collectively govern whether a conjugate is a viable candidate for further development. Anakinra (recombinant interleukin-1 receptor antagonist, IL-1Ra) is an approved anti-inflammatory biologic whose short systemic residence necessitates daily subcutaneous injection and is associated with steep peak-trough exposure fluctuations that, in chronic high-dose regimens, have been linked to IL-1Ra-derived systemic amyloidosis. PEGylation offers a chemically established route to increase the apparent molecular size of IL-1Ra and thereby reduce renal filtration and smooth exposure, but the structural and functional consequences of conjugation have never been characterized at residue resolution for this target─a gap that limits informed design choices between available chemistries. Here, we address this gap by establishing a head-to-head characterization framework comparing site-specific thiol-maleimide conjugation and random amino-coupling on a uniformly 15N-labeled recombinant IL-1Ra variant (M143V) that preserves all native conjugation sites and is potency-matched to Anakinra. Across a 5-20 kDa PEG ladder at a substoichiometric 0.5:1 PEG:protein feed, site-specific thiol-maleimide coupling yielded substantially higher conversion (∼81%) and a homogeneous single-species di-PEGylated (DoP 2) conjugate, whereas random amino-coupling produced heterogeneous mixtures across all PEG sizes (∼33-36% conversion, multiple degrees of polymerization). Purified single-species conjugates were benchmarked under a fixed IL-1β EC80 challenge in HEK-Blue reporter cells; all retained full maximal efficacy but exhibited chemistry- and size-dependent right-shifts in IC50, indicating steric modulation of receptor engagement rather than loss of function. To directly establish whether PEG attachment perturbs structural integrity, 2D 1H-15N HSQC NMR on the 15N-labeled thiol-PEG10 conjugate demonstrated a preserved global fold with localized chemical-shift perturbations near cysteine-proximal surface regions, confirming site-selective modification and intact binding scaffold. Together, these data establish the conjugation quality, antagonist activity, and structural integrity of the lead conjugate as the prerequisite characterization foundation for its further development and provide a transferable analytical framework for the rational design of PEGylated cytokine therapeutics.
2026-06-12 | Prolonged Infections and Inflammatory Diseases in Common Variable Immune Deficiency as a Cause of AA Amyloidosis.
Background/Objectives: AA amyloidosis is a serious complication of chronic inflammation, which may arise in the setting of inborn errors of immunity (IEIs) due to recurrent or persistent infections. Common variable immunodeficiency (CVID) is the most frequent symptomatic IEI in adults, yet its association with secondary AA amyloidosis remains rarely reported. Case presentation: We describe a 37-year-old male with a history of recurrent pneumonia, chronic sinusitis, and osteomyelitis with sepsis since childhood. At age 33, he developed bilateral pneumonia after COVID-19, followed by repeated lower respiratory tract infections. At age 36, nephrotic syndrome (proteinuria 10.69 g/day, hypoalbuminemia) led to kidney and gastric mucosa biopsies, which confirmed AA amyloidosis. Immunological workup revealed panhypogammaglobulinemia (IgG 0.1 g/L, IgA 0.01 g/L, IgM 0.28 g/L), markedly reduced switched memory B cells, and an inverted CD4+/CD8+ ratio. Chest CT showed bronchiectasis, bronchiolitis, and mediastinal lymphadenopathy. Whole-exome sequencing excluded known monogenic IEIs, autoinflammatory, or hereditary amyloidosis genes; a heterozygous likely pathogenic variant in ODAD2 (associated with primary ciliary dyskinesia) was considered incidental. A diagnosis of CVID with secondary AA amyloidosis was established. Conclusions: This case illustrates that CVID may remain undiagnosed for decades and present with secondary AA amyloidosis as the first major complication. In any patient with nephrotic syndrome and a history of recurrent or unusual infections, an IEI should be actively excluded. Early recognition of CVID and appropriate immunoglobulin replacement therapy can prevent infectious exacerbations and potentially halt amyloid progression.
2026-05-25 | Proline-rich, polybasic peptides are a structurally distinct class of amyloid-reactive peptides.
Systemic amyloidosis is a chronic, devastating illness caused by the build-up of misfolded proteins, leading to abdominothoracic organ dysfunction. Currently approved treatment options focus on preventing further amyloid accumulation. As such, there is a clinically unmet need for therapeutics that can opsonize tissue-deposited amyloid for clearance by phagocytic cells. We have developed a class of polybasic peptides that bind conserved properties of amyloid and amyloid-associated hypersulfated heparan sulfate, with high specificity. We have generated a novel structural class of polybasic peptides (termed PxR peptides) based on a proline-rich repeat strategy that demonstrates potency against amyloid. Amyloid-reactivity and specificity were probed using amyloid-laden and control tissue sections from mice and humans. Amyloid binding to synthetic fibrils and human patient-derived amyloid extracts was quantified using immunosorbent assays. PxR peptide stability in mouse and human serum was quantified using a bioactivity assay. PxR peptides were predicted to form a linear face of positive charges, which can bind with high specificity and potency to synthetic fibrils and amyloid extracts, and are resistant to serum proteases. Polybasic PxR peptides offer additional resources as pan-amyloid binding peptides for effective delivery of bioactive and amyloid-clearing therapeutics to amyloid.
antibodies
2026-08-29 | AA Amyloidosis Revealing HHV-8-Associated Multicentric Castleman Disease: A Case Report and Literature Review
Background/Objectives: Multicentric Castleman disease (MCD) is a rare systemic lymphoproliferative disorder driven by interleukin-6 (IL-6) dysregulation and frequently associated with human herpesvirus 8 (HHV-8) infection. AA amyloidosis is a severe complication of chronic inflammatory states, resulting from extracellular deposition of serum amyloid A (SAA) protein. We report a case of HHV-8-associated MCD revealed by AA amyloidosis with hepatic and salivary gland involvement. Methods: A 40-year-old Algerian woman with a six-year history of progressive gastrointestinal symptoms and chronic inflammation was evaluated for biopsy-proven AA amyloidosis involving the liver and minor salivary glands. Diagnostic workup included HHV-8 PCR, autoantibody screening, MEFV gene mutation analysis, bone marrow examination, and CT imaging. Results: HHV-8 viremia was positive (25,000 copies/mL), while autoimmune and genetic testing, including MEFV mutation screening, were negative. Clinical findings included chronic hypotension, normocytic anemia with hemolytic features, and subcentimeter lymphadenopathy on CT. A diagnosis of HHV-8-associated MCD with secondary AA amyloidosis was established. The patient was treated with rituximab (375 mg/m² weekly for four weeks) combined with valganciclovir, resulting in viral clearance, normalization of inflammatory markers, and improvement in hemoglobin. Conclusions: MCD should be considered in patients with unexplained chronic inflammation and AA amyloidosis. Early recognition and targeted therapy with rituximab are essential to prevent irreversible organ damage. Excisional lymph node biopsy with HHV-8 immunostaining is critical for definitive diagnosis.
2026-08-01 | Idiopathic AA Renal Amyloidosis Treated with Tocilizumab — A Case Report
Background Amyloidosis represents a heterogeneous group of disorders characterized by the deposition of misfolded protein. Among its subtypes, serum amyloid A (AA) amyloidosis arises when persistent systemic inflammation drives hepatic production of SAA. Excess SAA misfolds into insoluble fibrils that deposit in organs such as the kidneys, causing progressive proteinuria, loss of renal function and eventual renal failure. Standard management aims to control the underlying inflammation to reduce SAA production and halt further amyloid deposition. For example, interleukin-6 blockade with tocilizumab, which suppresses SAA production, has shown encouraging results in small series of patients with secondary amyloidosis. [1,2] In rare cases without an identifiable source of inflammation, however, no targeted therapies have been shown to be effective. Case Report We report a 48-year-old female first found incidentally at the age of 37 to have renal impairment. Over the past decade, her eGFR had declined to 12mL/min/1.73m 2 , with 3g/L of proteinuria. Renal biopsy in 2020 confirmed widespread AA amyloid deposits with severe interstitial fibrosis and 11/16 glomeruli globally sclerosed, with SAA concentrations exceeding 16,000ng/mL. Throughout her entire course, she had no infectious, rheumatologic or constitutional symptoms. Other than a RF titer of 30 IUx103/L, extensive investigations were negative, including bone marrow biopsy, rheumatologic markers (CCP, ANA, dsDNA, C3/C4, ANCA, ESR, CRP) and infectious serologies (hepatitis, syphilis, schistosoma, strongyloides, whipples, tuberculosis, HIV, HTLV, filariasis). A thorough genetic investigation was also negative including sequencing for the SAA1 gene, panels containing genes associated with hereditary amyloidosis and autoinflammatory diseases, as well as a research exome. A brief trial of colchicine was initially trialed but stopped due to worsening kidney function. Tocilizumab 160mg SC every 2 weeks was initiated in December 2024 in an attempt to suppress hepatic SAA production. A year after, SAA levels fell from >16,000 to 5,427ng/mL. Her GFR stabilized at 13 mL/min/1.73m 2 , and dialysis has not yet been required at the time of writing. Conclusion Idiopathic AA amyloidosis is a therapeutic challenge due to the condition’s rarity and lack of standard therapies. While there are numerous publications demonstrating the efficacy of tocilizumab in secondary AA amyloidosis,[1-3] our case is the first we are aware of, describing this therapeutic effect in idiopathic AA amyloidosis. This case underscores the central role of interleukin-6 in SAA production and may form the foundation for future studies with more patients over a longer duration to further explore the disease-modifying benefits of tocilizumab in idiopathic AA amyloidosis. References [1.] Okuda Y. Mod Rheumatol 2019;29:268-74. [2.] Courties A. Amyloid 2015;22:84-92. [3.] Yamagata A. BMC Nephrol 2017;18:377.
2026-07-01 | AA Amyloidosis in Africa: Epidemiology, Etiologies, Diagnostic Gaps, and Therapeutic Perspectives
ABSTRACT This review synthesizes epidemiological data from Algeria (378 cases), Tunisia (310 cases), Morocco (30 cases), Egypt (40 cases) and sub‑Saharan Africa (autopsy incidence 0.28‑0.57%). Tuberculosis remains the leading cause in all Maghreb countries, while Algeria shows a documented increase in autoinflammatory diseases; familial Mediterranean fever (FMF) predominates as the leading cause in Egypt. Diagnostic gaps include the absence of mass spectrometry in all African countries, limited anti‑AA immunohistochemistry in sub‑Saharan Africa, and no routine SAP scintigraphy. Therapeutic access is highly contrasted: adalimumab is available in several Maghreb countries, anakinra in Algeria (TRAPS approval 2025), and canakinumab is virtually absent. We propose national registries (based on the Egyptian FMF registry and the Armenian NAREG model), South‑North telepathology, and expanded access to biotherapies through biosimilars. Keywords: AA amyloidosis, Africa, diagnosis, SAP scintigraphy, Congo red, tuberculosis, FMF, autoinflammatory diseases, biotherapies.
2026-07-01 | The antibody-peptide fusion protein, AT-02, is an effective opsonin with pan-amyloid reactivity.
In systemic amyloidosis, the progressive accumulation of amyloid fibrils along with extracellular matrix components causes organ dysfunction, reduced quality of life, and is often fatal. Currently, twenty different proteins have been identified in systemic amyloid fibrils. Therapeutic elimination of tissue amyloid may improve organ function and patient outcomes. Amyloid-reactive immunoglobulins capable of stimulating cell-mediated clearance of amyloid deposits represent promising therapeutic strategies. AT-02 (zamubafusp alfa) is an immunoglobulin-peptide fusion protein comprising a humanized IgG1 and a pan-amyloid reactive peptide, p5R. AT-02 binds two ubiquitous components of all amyloids, namely amyloid fibrils and highly sulfated heparan sulfate glycans. This fusion protein exhibits specific reactivity with many amyloid types, obviating the need for individualized immunoglobulins for therapy. We demonstrate that AT-02 is an effective opsonin for amyloid by enhancing phagocytosis of amyloid extracts and inducing complement fixation. These data suggest that pan-amyloid binding reagents may provide novel treatment options for amyloid removal.
2026-06-25 | Inflammation in Cardiomyopathies: Cellular Mechanisms Across Cardiac Phenotype.
Cardiomyopathies are traditionally classified by structural and genetic phenotypes, but emerging evidence highlights chronic myocardial inflammation as a pivotal driver of disease progression across different etiologies. This review synthesizes the current literature on the cellular and molecular inflammatory mechanisms underlying hypertrophic cardiomyopathy, Anderson-Fabry disease, cardiac amyloidosis, arrhythmogenic cardiomyopathy, and dilated cardiomyopathy. Across these distinct conditions, endogenous triggers such as metabolic substrates, misfolded amyloid fibrils, mechanical stress, or viral genomes act as damage-associated molecular patterns. These stimuli activate innate and adaptive immune cascades, notably the Toll-like receptors, the NF-κB pathway, and the NLRP3 inflammasome. This immune activation establishes a pro-inflammatory microenvironment that promotes fibroblast reprogramming, myocardial edema, and progressive fibrotic or fibro-fatty remodeling. Inflammation is an active, core pathophysiological mechanism rather than a passive secondary bystander in cardiomyopathies. Recognizing these shared immune pathways provides a framework for improved risk stratification and highlights the potential for targeted immunomodulatory therapies to alter disease trajectories.
cell therapies
2026-03-23 | Development and characterization of chimeric antigen receptor macrophages for amyloid clearance.
Systemic amyloidosis is a protein folding disorder characterized by the extracellular deposition of protein fibrils in tissues and vital organs, leading to dysfunction and mortality. While there are monoclonal antibody-based therapies that promote cell-mediated amyloid clearance in various stages of clinical development, there are currently no treatment options which focus on reducing the tissue amyloid burden. Therefore, the urgent need for a transformative approach to facilitate amyloid clearance and restore organ function remains paramount. We demonstrate that a short, polybasic peptide (p5) can serve as a versatile recognition motif for chimeric antigen receptors in macrophages, enabling pan-amyloid binding and uptake. By comparing CH2- and CH3-spacer designs, quantifying glycan interactions, and establishing opsonization- and complement-dependent enhancement, we provide a blueprint for peptide-targeted CAR-M engineering beyond conventional scFv recognition. These findings broaden the repertoire of CAR targeting strategies and motivate translational studies of CAR-M for systemic amyloidosis, where established fibrils persist despite precursor-lowering therapies.
2024-02-26 | Kidney Transplantation in Patients With AA Amyloidosis: Outcomes in a French Multicenter Cohort.
Outcomes of kidney transplantation for patients with renal AA amyloidosis are uncertain, with reports of poor survival and high rates of disease recurrence. However, the data are inconclusive and mostly based on studies from the early 2000s and earlier. Retrospective multicenter cohort study. We searched the French national transplant database to identify all patients with renal AA amyloidosis who underwent kidney transplantation between 2008 and 2018. Age, cause of amyloidosis, use of biotherapies, and C-reactive protein levels. Outcomes were all-cause mortality and allograft loss. We also reported amyloidosis allograft recurrence, occurrence of acute rejection episodes, as well as infectious, cardiovascular, and neoplastic disease events. Kaplan-Meier estimator for mortality and cumulative incidence function method for allograft loss. Factors associated with patient and allograft survival were investigated using a Cox proportional hazards model and a cause-specific hazards model, respectively. 86 patients who received kidney transplants for AA amyloidosis at 26 French centers were included. The median age was 49.4 years (IQR, 39.7-61.1). The main cause of amyloidosis was familial Mediterranean fever (37 cases; 43%). 16 (18.6%) patients received biotherapy after transplantation. Patient survival rates were 94.0% (95% CI, 89.1-99.2) at 1 year and 85.5% (77.8-94.0) at 5 years after transplantation. Cumulative incidences of allograft loss were 10.5% (4.0-17.0) at 1 year and 13.0% (5.8-20.1) at 5 years after transplantation. Histologically proven AA amyloidosis recurrence occurred in 5 transplants (5.8%). An infection requiring hospitalization developed in 55.8% of cases, and there was a 27.9% incidence of acute allograft rejection. Multivariable analysis showed that C-reactive protein concentration at the time of transplantation was associated with patient survival (HR, 1.01; 95% CI, 1.00-1.02; P=0.01) and allograft survival (HR, 1.68; 95% CI, 1.10-2.57; P=0.02). The study lacked a control group, and the effect of biotherapies on transplantation outcomes could not be explored. This relatively contemporary cohort of patients who received a kidney transplant for AA amyloidosis experienced favorable rates of survival and lower recurrence rates than previously reported. These data support the practice of treating these patients with kidney transplantation for end-stage kidney disease. AA amyloidosis is a severe and rare disease. Kidney involvement is frequent and leads to end-stage kidney disease. Because of the involvement of other organs, these patients are often frail, which has raised concerns about their suitability for kidney transplantation. We reviewed all patients with AA amyloidosis nephropathy who underwent kidney transplantation in France in the recent era (2008-2018) and found that the outcomes after kidney transplantation were favorable, with 85.5% of patients still alive 5 years after transplantation, a survival rate that is comparable to the outcomes of patients receiving a transplant for other forms of kidney diseases. Recurrence of amyloidosis in the transplanted kidney was infrequent (5.8%). These data support the practice of kidney transplantation for patients with AA amyloidosis who experience kidney failure.
2024-01-12 | Extracellular vesicles as next-generation therapeutics and biomarkers in amyloidosis: a new frontier
Nanoparticles hold a great potential for therapeutic targeting due to their ability to improve the stability of encapsulated cargo and promote the transport of cargo across membranes to reach to the target site. Most commercially available nanomedicines are simple synthetic liposomes, however, there are numerous side effects due to their off-target delivery and rapid clearance from the bloodstream. Recently, attention has moved toward extracellular vesicles (EVs)–lipid bilayer enclosed particles released by cells (size ranging from 30 to 10,000 nm in diameter). EVs carry and transport lipids, proteins, and nucleic acids from their parental cells to recipient cells, hence they play a key role in intercellular communication. The ability of EVs to cross biological barriers including the blood brain barrier has generated significant attention to explore them as potential biomarkers and natural drug delivery vehicles for various therapeutics and small molecules. EVs have also been implicated in disease pathogenesis by transmitting pathogenic proteins between cells, making them promising biomarkers for disease diagnosis and monitoring. In this review, we will focus on the potential and challenges of EVs as biomarkers, drug delivery vehicles and next-generation therapeutics. Finally, we will explore misfolded protein disorders, amyloidosis, as a case study for how EVs may contribute to disease pathology and how EVs could be applied in the clinic as diagnostic and prognostic biomarkers of amyloid diseases.
2021-06-30 | Serum Amyloid A1 Induces Classically Activated Macrophages: A Role for Enhanced Fibril Formation
AA amyloidosis belongs to the group of amyloid diseases which can follow chronic inflammatory conditions of various origin. The disease is characterized by the deposition of insoluble amyloid fibrils formed by serum amyloid A1 (SAA1) leading eventually to organ failure. Macrophages are intimately involved in the fibrillogenesis as well as in the clearance of amyloid fibrils. In vivo, macrophages may occur as classically (M1) or alternatively activated (M2) macrophages. We investigate here how SAA1 might affect the macrophage phenotype and function. Gene microarray analysis revealed upregulation of 64 M1-associated genes by SAA1. M1-like polarization was further confirmed by the expression of the M1-marker MARCO, activation of the NF-κB transcription factor, and secretion of the M1-cytokines TNF-α, IL-6, and MCP-1. Additionally, we demonstrate here that M1-polarized macrophages exhibit enhanced fibrillogenic activity towards SAA1. Based on our data, we propose reconsideration of the currently used cellular amyloidosis models towards an in vitro model employing M1-polarized macrophages. Furthermore, the data suggest macrophage repolarization as potential intervention strategy in AA amyloidosis.
2021-05-14 | Kidney transplantation as a treatment of choice for AA amyloidosis due to periodic fever syndrome.
Renal AA amyloidosis is the most serious complication of periodic fever syndrome, which, inadequate suppression, due to persistent inflammation, leads to nephrotic syndrome and renal failure over several years. In most cases, periodic fever syndromes begin to manifest clinically in early childhood. Occurrence in adulthood is considered rare and is associated with a poorer clinical course. Kidney transplantation (KT) is an effective and safe treatment for end-stage chronic kidney disease (CKD) based on AA amyloidosis. In this paper, we present cases of two patients after deceased donor KT, who have been diagnosed with adult periodic fever syndrome. In the first one, diagnosis and treatment began in advanced stage of CKD and therefore underwent KT with compensated disease, while in the second patient, the disease manifested and diagnosed in the post-KT period. Timely initiation of treatment ensured protection of the graft from amyloid deposition.
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2025-12-01 | Gene immunotherapy regulated by astrocytic reactivity in a mouse model of amyloidosis
These results suggest that the GFAP promoter could control the production of therapeutics, such as rSol, in response to amyloid-induced astrocytic reactivity. Long-term studies will assess whether rSol prevents Aβ pathology progression in Tg-Aβ mice.
2005-04-20 | In vivo fragmentation of heparan sulfate by heparanase overexpression renders mice resistant to amyloid protein A amyloidosis.
Amyloid diseases encompass >20 medical disorders that include amyloid protein A (AA) amyloidosis, Alzheimer's disease, and type 2 diabetes. A common feature of these conditions is the selective organ deposition of disease-specific fibrillar proteins, along with the sulfated glycosaminoglycan, heparan sulfate. We have generated transgenic mice that overexpress human heparanase and have tested their susceptibility to amyloid induction. Drastic shortening of heparan sulfate chains was observed in heparanase-overproducing organs, such as liver and kidney. These sites selectively escaped amyloid deposition on experimental induction of inflammation-associated AA amyloidosis, as verified by lack of material staining with Congo Red, as well as lack of associated polysaccharide, whereas the same tissues from control animals were heavily infiltrated with amyloid. By contrast, the spleens of transgenic mice that failed to significantly overexpress heparanase contained heparan sulfate chains similar in size to those of control spleen and remained susceptible to amyloid deposition. Our findings provide direct in vivo evidence that heparan sulfate is essential for the development of amyloid disease.
1995-06-01 | Linkage of protection against amyloid fibril formation in the mouse to a single, autosomal dominant gene.
Inbred strains of mice provide a model for studies of the pathogenesis of amyloid A (AA) amyloidosis. All susceptible strains of mice described to date codominantly express two serum amyloid A (apoSAA) isoforms, apoSAA1 and apoSAA2, of which only apoSAA2 serves as a precursor for amyloid fibrils. In previous studies, we have shown that the CE/J strain, which produces a single, novel apoSAA isoform, apoSAACE/J, is amyloid resistant. In the present study amyloid-resistant CE/J females were mated with amyloid-susceptible CBA/J males to produce F1 hybrid offspring which were then backcrossed to the parental CBA/J mouse strain. Amyloid susceptibility was determined in 30 backcrossed mice 72 h after injection of murine amyloid enhancing factor and silver nitrate. ApoSAA isoforms in plasma were separated by isoelectric focusing gel electrophoresis and visualized after immunoblotting with anti-AA antiserum. Amyloid A fibrils in spleen homogenates were denatured by formic acid and AA protein was quantified by ELISA using anti-mouse apoSAA antibodies. Values < 5 apoSAA equivalent units were considered negative. 13 mice expressed an apoSAA1 and apoSAA2 doublet characteristic of CBA/J mice, whereas 17 mice, expressed the apoSAACE/J isoform codominantly with apoSAA1 and apoSAA2. The correlation of amyloid resistance to expression of the apoSAACE/J isoform was absolute (17/17 were negative; mean score 2.6 +/- 0.17 [standard error of the mean] apoSAA equivalent units) and the correlation between amyloid susceptibility and the expression of apoSAA2/apoSAA1 was also striking (12/13 were amyloid positive; mean score 47.9 +/- 9.0 [standard error of the mean] apoSAA equivalent units (P < 0.001). This is not significantly different from the 50% segregation of apoSAA phenotypes expected for linkage to a single gene. These results indicate that a single gene governs apoSAACE/J expression and thus confers protection against amyloid deposition even in the presence of apoSAA1 and apoSAA2 isoforms and show for the first time that resistance to AA amyloidosis is a dominant trait governed by a single gene.
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Drug Discovery Landscape
1 orphan drug designation for AA amyloidosis.
1 orphan drug designation for AA amyloidosis.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
eprodisate | small molecules | FDA | C. T. Development America, Inc. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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